bims-unfpre Biomed News
on Unfolded protein response
Issue of 2022‒09‒04
ten papers selected by
Susan Logue
University of Manitoba
  1. PIDDosome-SCAP crosstalk controls high-fructose-diet-dependent transition from simple steatosis to steatohepatitis.
  2. IRE1α overexpression in malignant cells limits tumor progression by inducing an anti-cancer immune response.
  3. Regulation of Blos1 by IRE1 prevents the accumulation of Huntingtin protein aggregates.
  4. Melatonin promotes sirtuin 1 expression and inhibits IRE1α-XBP1S-CHOP to reduce endoplasmic reticulum stress-mediated apoptosis in chondrocytes.
  5. Interactions between endoplasmic reticulum stress and extracellular vesicles in multiple diseases.
  6. Chronic activation of pDCs in autoimmunity is linked to dysregulated ER stress and metabolic responses.
  7. Goblet cells need some stress.
  8. AMPylation and Endoplasmic Reticulum Protein Folding Homeostasis.
  9. Keratin 8 is a scaffolding and regulatory protein of ERAD complexes.
  10. Loss of AID exacerbates the malignant progression of CLL.
  1. Cell Metab. 2022 Aug 23. pii: S1550-4131(22)00348-5. [Epub ahead of print]
    PIDDosome-SCAP crosstalk controls high-fructose-diet-dependent transition from simple steatosis to steatohepatitis.
    Ju Youn Kim, Lily Q Wang, Valentina C Sladky, Tae Gyu Oh, Junlai Liu, Kaitlyn Trinh, Felix Eichin, Michael Downes, Mojgan Hosseini, Etienne D Jacotot, Ronald M Evans, Andreas Villunger, Michael Karin.
      Sterol deficiency triggers SCAP-mediated SREBP activation, whereas hypernutrition together with ER stress activates SREBP1/2 via caspase-2. Whether these pathways interact and how they are selectively activated by different dietary cues are unknown. Here, we reveal regulatory crosstalk between the two pathways that controls the transition from hepatosteatosis to steatohepatitis. Hepatic ER stress elicited by NASH-inducing diets activates IRE1 and induces expression of the PIDDosome subunits caspase-2, RAIDD, and PIDD1, along with INSIG2, an inhibitor of SCAP-dependent SREBP activation. PIDDosome assembly activates caspase-2 and sustains IRE1 activation. PIDDosome ablation or IRE1 inhibition blunt steatohepatitis and diminish INSIG2 expression. Conversely, while inhibiting simple steatosis, SCAP ablation amplifies IRE1 and PIDDosome activation and liver damage in NASH-diet-fed animals, effects linked to ER disruption and preventable by IRE1 inhibition. Thus, the PIDDosome and SCAP pathways antagonistically modulate nutrient-induced hepatic ER stress to control non-linear transition from simple steatosis to hepatitis, a key step in NASH pathogenesis.
    Keywords:  ER stress; IRE1; NAFLD; NASH; PIDDosome; SCAP; SREBP; caspase-2; steatohepatitis; steatosis
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.005
  2. Oncoimmunology. 2022 ;11(1): 2116844
    IRE1α overexpression in malignant cells limits tumor progression by inducing an anti-cancer immune response.
    Adriana Martinez-Turtos, Rachel Paul, Manuel Grima-Reyes, Hussein Issaoui, Adrien Krug, Rana Mhaidly, Jozef P Bossowski, Johanna Chiche, Sandrine Marchetti, Els Verhoeyen, Eric Chevet, Jean-Ehrland Ricci.
      IRE1α is one of the three ER transmembrane transducers of the Unfolded Protein Response (UPR) activated under endoplasmic reticulum (ER) stress. IRE1α activation has a dual role in cancer as it may be either pro- or anti-tumoral depending on the studied models. Here, we describe the discovery that exogenous expression of IRE1α, resulting in IRE1α auto-activation, did not affect cancer cell proliferation in vitro but resulted in a tumor-suppressive phenotype in syngeneic immunocompetent mice. We found that exogenous expression of IRE1α in murine colorectal and Lewis lung carcinoma cells impaired tumor growth when syngeneic tumor cells were subcutaneously implanted in immunocompetent mice but not in immunodeficient mice. Mechanistically, the in vivo tumor-suppressive effect of overexpressing IRE1α in tumor cells was associated with IRE1α RNAse activity driving both XBP1 mRNA splicing and regulated IRE1-dependent decay of RNA (RIDD). We showed that the tumor-suppressive phenotype upon IRE1α overexpression was characterized by the induction of apoptosis in tumor cells along with an enhanced adaptive anti-cancer immunosurveillance. Hence, our work indicates that IRE1α overexpression and/or activation in tumor cells can limit tumor growth in immunocompetent mice. This finding might point toward the need of adjusting the use of IRE1α inhibitors in cancer treatments based on the predominant outcome of the RNAse activity of IRE1α.
    Keywords:  Cancer; IRE1α; RIDD; UPR; XBP1s; anti-cancer immunosurveillance; apoptosis
    DOI:  https://doi.org/10.1080/2162402X.2022.2116844
  3. Mol Biol Cell. 2022 Aug 31. mbcE22070281
    Regulation of Blos1 by IRE1 prevents the accumulation of Huntingtin protein aggregates.
    Donghwi Bae, Rachel Elizabeth Jones, Katherine M Piscopo, Mitali Tyagi, Jason D Shepherd, Julie Hollien.
      Huntington's disease is characterized by accumulation of the aggregation-prone mutant Huntingtin (mHTT) protein. Here, we show that expression of exon 1 of mHTT in mouse cultured cells activates IRE1, the transmembrane sensor of stress in the endoplasmic reticulum, leading to degradation of the Blos1 mRNA and repositioning of lysosomes and late endosomes toward the microtubule organizing center. Overriding Blos1 degradation results in excessive accumulation of mHTT aggregates in both cultured cells and primary neurons. Although mHTT is degraded by macroautophagy when highly expressed, we show that prior to the formation of large aggregates, mHTT is degraded via an ESCRT-dependent, macroautophagy-independent pathway consistent with endosomal microautophagy. This pathway is enhanced by Blos1 degradation and appears to protect cells from a toxic, less aggregated form of mHTT.
    DOI:  https://doi.org/10.1091/mbc.E22-07-0281
  4. Front Pharmacol. 2022 ;13 940629
    Melatonin promotes sirtuin 1 expression and inhibits IRE1α-XBP1S-CHOP to reduce endoplasmic reticulum stress-mediated apoptosis in chondrocytes.
    Kunpeng Qin, Hao Tang, Yi Ren, Di Yang, Yetian Li, Wei Huang, Yunfeng Wu, Zongsheng Yin.
      Osteoarthritis (OA) is the most common chronic disease characterized by a loss of chondrocytes and the degeneration of cartilage. Inflammation plays an important role in the pathogenesis and progression of OA via the activation of the endoplasmic reticulum (ER) stress signaling pathway. In this study, we stimulated human primary chondrocytes with lipopolysaccharide (LPS) to reduce cell viability and induce chondrocyte apoptosis. LPS-stimulated human primary chondrocytes induced ER stress and significantly upregulated the ER chaperone glucose-regulated protein 78 (GRP78) and increased the expression level of C/EBP-homologous protein (CHOP), a key mediator of ER stress--induced apoptosis. Interestingly, melatonin treatment attenuated ER stress-mediated chondrocyte apoptosis. Melatonin inhibited the expression of cleaved caspase-3, cleaved caspase-10, Bax, CHOP, GRP78, cleaved caspase-4, phospho-inositol-requiring enzyme 1α (P-IRE1α), and spliced X-box-binding protein 1 (XBP1S). In an anterior cruciate ligament transection mouse model of OA, melatonin (50 and 150 mg/kg) dose-dependently relieved joint cartilage degeneration and inhibitied of chondrocyte apoptosis. Immunohistochemical analysis indicated that melatonin could promote SIRT1 the expression and inhibit CHOP and cleaved caspase-3 expression in OA mice. In conclusion, our findings demonstrate for the first time that melatonin inhibits the IRE1α-XBP1S-CHOP signaling pathway by promoting the expression of SIRT1 in LPS-treated human chondrocytes and delaying OA progression in vivo.
    Keywords:  IRE1α--XBP1S--CHOP; apoptosis; endoplasmic reticulum stress; melatonin; osteoarthritis
    DOI:  https://doi.org/10.3389/fphar.2022.940629
  5. Front Immunol. 2022 ;13 955419
    Interactions between endoplasmic reticulum stress and extracellular vesicles in multiple diseases.
    Jingyao Ye, Xuehong Liu.
      Immune responses can severely perturb endoplasmic reticulum (ER) function. As a protein-folding factory and dynamic calcium storage compartment, the ER plays a pivotal role in resisting pathogens and in the development of autoimmune diseases and various other diseases, including cancer, cardiovascular, neurological, orthopedic, and liver-related diseases, metabolic disorders, etc. In recent years, an increasing number of studies have shown that extracellular vesicles (EVs) play important roles in these conditions, suggesting that cells carry out some physiological functions through EVs. The formation of EVs is dependent on the ER. ER stress, as a state of protein imbalance, is both a cause and consequence of disease. ER stress promotes the transmission of pathological messages to EVs, which are delivered to target cells and lead to disease development. Moreover, EVs can transmit pathological messages to healthy cells, causing ER stress. This paper reviews the biological functions of EVs in disease, as well as the mechanisms underlying interactions between ER stress and EVs in multiple diseases. In addition, the prospects of these interactions for disease treatment are described.
    Keywords:  UPR signaling pathways; endoplasmic reticulum stress; extracellular vesicles; interactions; multiple diseases
    DOI:  https://doi.org/10.3389/fimmu.2022.955419
  6. J Exp Med. 2022 Nov 07. pii: e20221085. [Epub ahead of print]219(11):
    Chronic activation of pDCs in autoimmunity is linked to dysregulated ER stress and metabolic responses.
    Vidyanath Chaudhary, Marie Dominique Ah Kioon, Sung-Min Hwang, Bikash Mishra, Kimberly Lakin, Kyriakos A Kirou, Jeffrey Zhang-Sun, R Luke Wiseman, Robert F Spiera, Mary K Crow, Jessica K Gordon, Juan R Cubillos-Ruiz, Franck J Barrat.
      Plasmacytoid dendritic cells (pDCs) chronically produce type I interferon (IFN-I) in autoimmune diseases, including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). We report that the IRE1α-XBP1 branch of the unfolded protein response (UPR) inhibits IFN-α production by TLR7- or TLR9-activated pDCs. In SSc patients, UPR gene expression was reduced in pDCs, which inversely correlated with IFN-I-stimulated gene expression. CXCL4, a chemokine highly secreted in SSc patients, downregulated IRE1α-XBP1-controlled genes and promoted IFN-α production by pDCs. Mechanistically, IRE1α-XBP1 activation rewired glycolysis to serine biosynthesis by inducing phosphoglycerate dehydrogenase (PHGDH) expression. This process reduced pyruvate access to the tricarboxylic acid (TCA) cycle and blunted mitochondrial ATP generation, which are essential for pDC IFN-I responses. Notably, PHGDH expression was reduced in pDCs from patients with SSc and SLE, and pharmacological blockade of TCA cycle reactions inhibited IFN-I responses in pDCs from these patients. Hence, modulating the IRE1α-XBP1-PHGDH axis may represent a hitherto unexplored strategy for alleviating chronic pDC activation in autoimmune disorders.
    DOI:  https://doi.org/10.1084/jem.20221085
  7. J Clin Invest. 2022 Sep 01. pii: e162030. [Epub ahead of print]132(17):
    Goblet cells need some stress.
    Malin Ev Johansson, Gunnar C Hansson.
      The intestinal tract is protected by epithelium-covering mucus, which is constantly renewed by goblet cells, a specialized type of epithelial cell. Mucus is largely composed of MUC2 mucin, an enormous molecule that poses a high demand on the endoplasmic reticulum (ER) for proper folding and protein assembly, creating a challenge for the secretory machinery in goblet cells. In this issue of the JCI, Grey et al. reveal that the ER resident protein and folding sensor ERN2 (also known as IRE1β) was instrumental for goblet cells to produce sufficient amounts of mucus to form a protective mucus layer. In the absence of ERN2, mucus production was reduced, impairing the mucus barrier, which allowed bacteria to penetrate and cause an epithelial cell stress response. This study emphasizes the importance of a controlled unfolded protein response (UPR) for goblet cell secretion.
    DOI:  https://doi.org/10.1172/JCI162030
  8. Cold Spring Harb Perspect Biol. 2022 Aug 30. pii: a041265. [Epub ahead of print]
    AMPylation and Endoplasmic Reticulum Protein Folding Homeostasis.
    Luke A Perera, David Ron.
      The endoplasmic reticulum (ER)-localized Hsp70 chaperone, BiP, undergoes a rapid, reversible and inactivating post-translational modification. This covalent modification complements the slower, conventional unfolded protein response (UPR) in matching the supply of active Hsp70 chaperone to the protein folding demand within the ER lumen. Long believed to be ADP-ribosylation, we now know this modification to be AMPylation (adenylylation) of BiP's threonine 518. Here, we review the discovery of the responsible enzyme (the Fic domain-containing protein FICD), the structural and biochemical basis of the inactivating modification and the discovery of FICD's dual role as the enzyme that both AMPylates and deAMPylates BiP. The structural basis of BiP recognition by FICD and recent in vitro insights into oligomeric state-mediated regulation of FICD's antagonistic enzymatic activities are also reviewed, the latter in the context of how such a regulatory system may arise in cells. Last, we consider the physiological significance of BiP AMPylation and speculate on the fitness benefits of this metazoan-specific adaptation.
    DOI:  https://doi.org/10.1101/cshperspect.a041265
  9. Cell Mol Life Sci. 2022 Sep;79(9): 503
    Keratin 8 is a scaffolding and regulatory protein of ERAD complexes.
    Iwona Maria Pranke, Benoit Chevalier, Aiswarya Premchandar, Nesrine Baatallah, Kamil F Tomaszewski, Sara Bitam, Danielle Tondelier, Anita Golec, Jan Stolk, Gergely L Lukacs, Pieter S Hiemstra, Michal Dadlez, David A Lomas, James A Irving, Agnes Delaunay-Moisan, Eelco van Anken, Alexandre Hinzpeter, Isabelle Sermet-Gaudelus, Aleksander Edelman.
      Early recognition and enhanced degradation of misfolded proteins by the endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD) cause defective protein secretion and membrane targeting, as exemplified for Z-alpha-1-antitrypsin (Z-A1AT), responsible for alpha-1-antitrypsin deficiency (A1ATD) and F508del-CFTR (cystic fibrosis transmembrane conductance regulator) responsible for cystic fibrosis (CF). Prompted by our previous observation that decreasing Keratin 8 (K8) expression increased trafficking of F508del-CFTR to the plasma membrane, we investigated whether K8 impacts trafficking of soluble misfolded Z-A1AT protein. The subsequent goal of this study was to elucidate the mechanism underlying the K8-dependent regulation of protein trafficking, focusing on the ERAD pathway. The results show that diminishing K8 concentration in HeLa cells enhances secretion of both Z-A1AT and wild-type (WT) A1AT with a 13-fold and fourfold increase, respectively. K8 down-regulation triggers ER failure and cellular apoptosis when ER stress is jointly elicited by conditional expression of the µs heavy chains, as previously shown for Hrd1 knock-out. Simultaneous K8 silencing and Hrd1 knock-out did not show any synergistic effect, consistent with K8 acting in the Hrd1-governed ERAD step. Fractionation and co-immunoprecipitation experiments reveal that K8 is recruited to ERAD complexes containing Derlin2, Sel1 and Hrd1 proteins upon expression of Z/WT-A1AT and F508del-CFTR. Treatment of the cells with c407, a small molecule inhibiting K8 interaction, decreases K8 and Derlin2 recruitment to high-order ERAD complexes. This was associated with increased Z-A1AT secretion in both HeLa and Z-homozygous A1ATD patients' respiratory cells. Overall, we provide evidence that K8 acts as an ERAD modulator. It may play a scaffolding protein role for early-stage ERAD complexes, regulating Hrd1-governed retrotranslocation initiation/ubiquitination processes. Targeting K8-containing ERAD complexes is an attractive strategy for the pharmacotherapy of A1ATD.
    Keywords:  Cytoskeleton; Epithelium; Intermediary filaments; Protein complexes fractionation; Protein–protein interaction; Synthetic lethality
    DOI:  https://doi.org/10.1007/s00018-022-04528-3
  10. Leukemia. 2022 Aug 30.
    Loss of AID exacerbates the malignant progression of CLL.
    Avery C Lee, Sai Ravi Pingali, Javier A Pinilla-Ibarz, Michael L Atchison, Constantinos Koumenis, Yair Argon, Andrei Thomas-Tikhonenko, Carl De Trez, Chih-Chi Andrew Hu, Chih-Hang Anthony Tang.
      Activation-induced cytidine deaminase (AID) has been implicated as both a positive and a negative factor in the progression of B cell chronic lymphocytic leukemia (CLL), but the role that it plays in the development and progression of this disease is still unclear. We generated an AID knockout CLL mouse model, AID-/-/Eμ-TCL1, and found that these mice die significantly earlier than their AID-proficient counterparts. AID-deficient CLL cells exhibit a higher ER stress response compared to Eμ-TCL1 controls, particularly through activation of the IRE1/XBP1s pathway. The increased production of secretory IgM in AID-deficient CLL cells contributes to their elevated expression levels of XBP1s, while secretory IgM-deficient CLL cells express less XBP1s. This increase in XBP1s in turn leads AID-deficient CLL cells to exhibit higher levels of B cell receptor signaling, supporting leukemic growth and survival. Further, AID-/-/Eμ-TCL1 CLL cells downregulate the tumor suppressive SMAD1/S1PR2 pathway and have altered homing to non-lymphoid organs. Notably, CLL cells from patients with IgHV-unmutated disease express higher levels of XBP1s mRNA compared to those from patients with IgHV-mutated CLL. Our studies thus reveal novel mechanisms by which the loss of AID leads to worsened CLL and may explain why unmutated CLL is more aggressive than mutated CLL.
    DOI:  https://doi.org/10.1038/s41375-022-01663-5
This page is being maintained by Thomas Krichel. It was last updated on 2022‒09‒04 at 21:49:05.